Coactivators

Abstract In contrast to Chapters 5 through 12, which described genetic defects involving trans-acting factors that directly bind to DNA and either activate or repress the transcription of target genes, this chapter will focus on disorders involving mutations in genes encoding coactivators, proteins that exert their effects on transcription strictly via protein-protein interactions (see Chapter 3). Coactivators function by establishing physical interactions between sequence-specific DNA-binding proteins and the transcription initiation complex containing Pol II and associated general transcription factors. In addition, many coactivators contain catalytic domains involved in the enzymatic modification of other regulatory proteins or chromatin. Both DNA-binding proteins and coactivators share in common the characteristic that they each regulate only a subset of the Pol II-transcribed sequences in the genome. Whereas the specificity of DNA binding proteins is based on the presence of high-affinity binding-site sequences in proximity to target genes, the specificity of coactivator function must be based in turn on the nature of the DNA-binding proteins that have assembled at regulatory sequences. Because multiple, relatively low-affinity interactions may be involved in determining coactivator interactions, the rules defining coactivator specificity may be more difficult to delineate than those determining DNA-binding activity.